Adoptive cell transfer (ACT) of cytotoxic T lymphocytes is being studied as a potent treatment strategy for cancers that are refractory to standard chemotherapy and radiation therapy. Clinical advances have been made in patients with metastatic melanoma using autologous tumor-infiltrating lymphocytes (TILs) and in several B-cell malignancies using autologous chimeric antigen receptor (CAR)-modified T cells1. Methods used to predict or monitor the activity of infused T cells in patients provide useful but limited data related to treatment efficacy. Current practices involve serum profiling of cytokines associated with T cell activation, direct enumeration of tumor-specific T cell numbers in peripheral circulation, and tumor biopsies2,3. Changes in serum cytokine levels, while useful, likely reflect a broader, systemic immune response, illustrating not only the activation of adoptively transferred T cells, but also their effects on neighboring immune cells and dying tumor cells4. Similarly, while the quantification of adoptively transferred cells in circulation provides useful information regarding their proliferation, researchers and clinicians are blind as to whether the dynamism in T cell numbers relates to expansion at the primary tumor site, metastatic foci, or at off-tumor sites5.
The imaging modalities with the highest potential for whole-body visualization of cell trafficking in humans are magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), PET/CT, or PET/MRI techniques for detection of labeled cells and coregistration of anatomical information of the body8-10. PET (positron emission graphy) is particularly amenable to clinical use as it enables non-invasive, highly sensitive, repetitive, and quantitative imaging of positron-emitting, target-specific probes. The introduction of microPET for small animal imaging has similarly made PET amenable to pre-clinical studies11. On-going activity of ACT against both on- and off-tumor sites can therefore be monitored in vivo by quantitative, radiotracer-based imaging of T cell distribution and expansion upon interaction with target antigen-expressing cells2,10,12. However, previous attempts to systemically monitor ACT in patients have yet to be adopted13. Passive labeling of T cells with positron emitting probes ex vivo has been used to monitor the early-stage migration of infused T cells but suffers from potential inaccuracies due to signals from dead or dying cells, probe dilution upon cell division, and a limited ability to track cells over extended periods of time due to short probe half-life10.